Genetically determined proteolytic cleavage modulates alpha7beta1 integrin function.
The dystrophin-glycoprotein complex and the alpha7beta1 integrin are trans-sarcolemmal linkage systems that connect and transduce contractile forces between muscle fibers and the extracellular matrix. alpha7beta1 is the major laminin binding integrin in skeletal muscle. Different functional variants of this integrin are generated by alternative splicing and post-translational modifications such as glycosylation and ADP-ribosylation. Here we report a species-specific difference in alpha7 chains that results from an intra-peptide proteolytic cleavage, by a serine protease, at the 603RRQ605 site. Site-directed mutagenesis of RRQ to GRQ prevents this cleavage. This RRQ sequence in the alpha7 integrin chain is highly conserved among vertebrates but it is absent in mice. Protein structure modeling indicates this cleavage site is located in an open region between the beta-propeller and thigh domains of the alpha7 chain. Compared with the non-cleavable alpha7 chain, the cleaved form enhances cell adhesion and spreading on laminin. Cleavage of the alpha7 chain is elevated upon myogenic differentiation, and this cleavage may be mediated by urokinase-type plasminogen activator. These results suggest proteolytic cleavage is a novel mechanism that regulates alpha7 integrin functions in skeletal muscle, and that the generation of such cleavage sites is another evolutionary mechanism for expanding and modifying protein functions.
Liu
Jianming
J
Department of Cell and Developmental Biology, University of Illinois, Urbana, Illinois 61801, USA.
Gurpur
Praveen B
PB
Kaufman
Stephen J
SJ
D017398:Alternative Splicing / Q000502:physiology; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D016466:CHO Cells; D002454:Cell Differentiation / Q000502:physiology*; D006224:Cricetinae; D003412:Cricetulus; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism; D006801:Humans; D039001:Integrin alpha Chains / Q000235:genetics / Q000378:metabolism*; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D007797:Laminin / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
D015703:Antigens, CD; D016189:Dystrophin; D039001:Integrin alpha Chains; D016023:Integrins; D007797:Laminin; C085725:integrin alpha7; D014568:Urokinase-Type Plasminogen Activator; C082908:integrin alpha7beta1